The broad objective of this project is to contribute to the understanding of relationships between metabolism and toxicity of pesticides in vertebrates. Particular emphasis is on metabolic and toxic action of organophosphorus insecticides. Recent studies have provided plausible biochemical mechanisms for the relative resistance of fish to poisoning by methyl parathion, for the greater susceptibility of young animals to poisoning by these compounds, and for the synergism of acute toxicity of organophosphates that compete for non-critical sites of loss. Evidence has been obtained that indicates that piperonyl butoxide which protects against acute toxicity of methyl parathion may increase the concentration and duration of tissue residues of this insecticide. Further studies will examine this possibility in more detail and with other insecticides. Studies of metabolic or interactions that may result from dermal exposure to organophosphate insecticides will be studied, and tests for possible functional toxicity of "leaving groups" of phosphate insecticides of relatively low acute toxicity will be initiated. These studies provide basic information concerning interactions and metabolism of pesticides which may be useful in predicting conditions in which man and other non-target species will be unusually susceptible to poisoning, and may point to compounds or modes of use that will minimize risks to health or environmental accumulation or effects.